Alcohol is one of the most commonly consumed psychoactive substances in the USA. It is used by 61% of the population, 7.4% of who meet criteria (APA DSM IV, 1994) for alcohol abuse or dependence (Grant, 1994). Despite its widespread use and many years of research, the neuroanatomical targets of acute doses of alcohol remain unclear. A better understanding of these targets may explain why some people drink alcohol excessively and develop alcohol abuse problems, whereas others do not. One reason for individual differences in the susceptibility to develop alcohol use disorders may be related to the subjective effects the drug produces: some people experience predominantly positive stimulant-like effects while others report only sedative effects. Individuals who experience stimulant-like effects report more "liking" of drug effects and they are more likely to consume alcohol in a preference test. Here, we propose to use brain imaging techniques to analyze patterns of brain activation in healthy volunteers who differ in their subjective responses to alcohol. The specific goals of this project are: 1) To identify the neuroanatomical targets of acute doses of alcohol (0, 40, 80mg%) using functional magnetic resonance imaging, and 2) To compare patterns of neural activation between individuals who report stimulant-like effects of alcohol and those who do not. We will use non-linear regression techniques to identify drug-induced changes in resting state signal after drug administration. In a sample of 42 light-moderate drinkers, we hypothesize that alcohol will produce dose-related signal changes in the nucleus accumbens, ventral tegmentum, caudate, putamen, amygdala, anterior cingulate, prefrontal cortex and cerebellum. Further we hypothesize that individuals who experience stimulation will exhibit greater signal change in the nucleus accumbens, ventral tegmentum, cingulate and prefrontal cortex whereas individuals who do not experience stimulation i.e., predominantly sedation, will exhibit greater signal change in the amygdala, striatum and cerebellum. The findings of this novel project will be fundamental to understanding how alcohol acts in the brain and how neural responses to alcohol influence the development of alcoholism. The research will improve our understanding of how individuals vary in their responses to alcohol and will contribute to our understanding of the etiology of alcoholism. This innovative project will bring together methodologies in the fMRI and alcohol research fields, and combines the experience of leading researchers in the drug abuse, alcoholism and imaging fields. PUBLIC HEALTH RELEVANCE: The neuroanatomical targets of acute doses of alcohol are unclear, but knowledge of these targets may help to explain why some people drink alcohol excessively and develop alcohol abuse problems, whereas others do not. Individual differences in susceptibility for alcohol use disorder may correspond to different actions of the drug in the brain and different subjective experiences. In this project we will use functional magnetic resonance imaging to identify the neuroanatomical targets of acute doses of alcohol in healthy human participants. We will compare patterns of neural activation after alcohol between individuals who report either feeling stimulated or feeling sedated after alcohol. These findings will be fundamental to understanding how alcohol acts in the brain and how neural responses to alcohol influence the development of alcoholism.